Humans and other warm-blooded animals can be afflicted by a number of bone-related disorders. Such disorders range from bone fractures, to debilitating diseases such as osteoporosis. While in healthy individuals, bone growth generally proceeds normally and fractures heal without the need for pharmacological intervention, in certain instances bones may become weakened or may fail to heal properly. For example, healing may proceed slowly in the elderly and in patients undergoing treatment with corticosteroids (e.g., transplant patients). Osteoporosis is a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue. Osteoporosis can generally be defined as the reduction in the quantity of bone, or the atrophy of skeletal tissue; marrow and bone spaces become larger, fibrous binding decreases, and compact bone becomes fragile. Another bone related disorder is osteoarthritis, which is a disorder of the movable joints characterized by deterioration and abrasion of articular cartilage, as well as by formation of new bone at the joint surface.
While a variety of treatments are available for such bone-related disorders, none of the treatments provide optimum results. One of the difficulties facing individuals who treat bone-related disorders is a lack of complete understanding of bone metabolism and of the bone-related disorders. A key to such understanding is identifying and characterizing each of the components involved in bone growth. Bone morphogenetic proteins (BMPs) have been demonstrated to play a role in bone formation and development (Wozney, J. M., Molec. Reproduct. and Develop., 32: 160-167 (1992)).
Furthermore, the role of BMPs may not be limited to their role in bone. The finding that the BMPs are found at significant concentrations in other tissues such as brain and kidney (Wall, N. A., Blessing, M., Wright, C. V. E., and Hogan, B. L. M., J Cell Biol., 120: 493-502 (1993); Ozkaynak, E., Schnegelsberg, P. N. J., Jin, D. F., Clifford, G. M., Warren, F. D., Drier, E. A., and Oppermann, H., J. Biol. Chem., 267: 25220-25227 (1992); Lyons, K. M., Jones, C. M., and Hogan, B. L. M., Trends in Genetics, 7: 408-412 (1991)) suggests that they may play additional roles in development and differentiation. In support of this, BMPs have recently been found to promote nerve cell differentiation (Basler, K., Edlund, T., Jessell, T. M., and Yamada, T., Cell, 73: 687-702 (1993); Paralkar, V. M., Weeks, B. S., Yu, Y. M., Kleinman, H. K., and Reddi, A. H., J. Cell Biol., 119: 1721-1728 (1992)).
A BMP initiates its biological effect on cells by binding to a specific BMP receptor expressed on the plasma membrane of a BMP-responsive cell. A receptor is a protein, usually spanning the cell membrane, which binds to a ligand from outside the cell, and as a result of that binding sends a signal to the inside of the cell which alters cellular function. In this case, the ligand is the protein BMP, and the signal induces the differentiation of the cell to produce cartilage and bone.
Because of the ability of a BMP receptor to specifically bind BMPs, purified BMP receptor compositions will be useful in diagnostic assays for BMPs, as well as in raising antibodies to the BMP receptor for use in diagnosis and therapy. In addition, purified BMP receptor compositions may be used directly in therapy to bind or scavenge BMPs, thereby providing a means for regulating the bone formation and development activities of BMPs. In order to study the structural and biological characteristics of BMP receptors and the role played by BMPs in the responses of various cell populations to BMPs during bone growth/formation stimulation, or to use a BMP receptor effectively in therapy, diagnosis, or assay, purified compositions of BMP receptor are needed. Such compositions, however, are obtainable in practical yields only by cloning and expressing genes encoding the receptors using recombinant DNA technology. Efforts to purify BMP receptors for use in biochemical analysis or to clone and express mammalian genes encoding BMP receptors have been impeded by lack of a suitable source of receptor protein or mRNA. Prior to the present invention, no cell lines were known to express high levels of BMP receptor constitutively and continuously, which precluded purification of the receptor for protein sequencing or construction of genetic libraries for direct expression cloning. Availability of the BMP receptor sequence will make it possible to generate cell lines with high levels of recombinant BMP receptor for biochemical analysis and use in screening experiments.
Based on the foregoing, there is a need for a BMP receptor DNA sequence and an isolated BMP receptor protein encoded by this sequence.